Personalized anesthesia and precision medicine: a comprehensive review of genetic factors, artificial intelligence, and patient-specific factors.

Precision medicine, characterized by the personalized integration of a patient's genetic blueprint and clinical history, represents a dynamic paradigm in healthcare evolution. The emerging field of personalized anesthesia is at the intersection of genetics and anesthesiology, where anesthetic care will be tailored to an individual's genetic make-up, comorbidities and patient-specific factors. Genomics and biomarkers can provide more accurate anesthetic protocols, while artificial intelligence can simplify anesthetic procedures and reduce anesthetic risks, and real-time monitoring tools can improve perioperative safety and efficacy. The aim of this paper is to present and summarize the applications of these related fields in anesthesiology by reviewing them, exploring the potential of advanced technologies in the implementation and development of personalized anesthesia, realizing the future integration of new technologies into clinical practice, and promoting multidisciplinary collaboration between anesthesiology and disciplines such as genomics and artificial intelligence.

TCMSSD: A comprehensive database focused on syndrome standardization.

BACKGROUD: Quantitative and standardized research on syndrome differentiation has always been at the forefront of modernizing Traditional Chinese Medicine (TCM) theory. However, the majority of existing databases primarily concentrate on the network pharmacology of herbal prescriptions, and there are limited databases specifically dedicated to TCM syndrome differentiation. PURPOSE: In response to this gap, we have developed the Traditional Chinese Medical Syndrome Standardization Database (TCMSSD, http://tcmssd.ratcm.cn). METHODS: TCMSSD is a comprehensive database that gathers data from various sources, including TCM literature such as TCM Syndrome Studies (Zhong Yi Zheng Hou Xue) and TCM Internal Medicine (Zhong Yi Nei Ke Xue) and various public databases such as TCMID and ETCM. In our study, we employ a deep learning approach to construct the knowledge graph and utilize the BM25 algorithm for syndrome prediction. RESULTS: The TCMSSD integrates the essence of TCM with the modern medical system, providing a comprehensive collection of information related to TCM. It includes 624 syndromes, 133,518 prescriptions, 8,073 diseases (including 1,843 TCM-specific diseases), 8,259 Chinese herbal medicines, 43,413 ingredients, 17,602 targets, and 8,182 drugs. By analyzing input data and comparing it with the patterns and characteristics recorded in the database, the syndrome prediction tool generates predictions based on established correlations and patterns. CONCLUSION: The TCMSSD fills the gap in existing databases by providing a comprehensive resource for quantitative and standardized research on TCM syndrome differentiation and laid the foundation for research on the biological basis of syndromes.

Identification of autophagy-associated circRNAs in sepsis-induced cardiomyopathy of mice.

Circular RNAs (circRNAs) play a role in sepsis-related autophagy. However, the role of circRNAs in autophagy after sepsis-induced cardiomyopathy (SICM) is unknown, so we explored the circRNA expression profiles associated with autophagy in an acute sepsis mouse model. At a dose of 10 mg/kg, mice were intraperitoneally administered with lipopolysaccharides. The myocardial tissue was harvested after 6 h for microarray analysis, qRT-PCR, and western blotting. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis were evaluated, and a competing endogenous RNA network was constructed, to evaluate the role of circRNAs related to autophagy in SICM. In total, 1,735 differently expressed circRNAs were identified in the LPS-treated group, including 990 upregulated and 745 downregulated circRNAs. The expression level of the autophagy-specific protein p62 decreased, while the ratio of LC3 II to LC3 I increased. Additionally, 309 mRNAs and 187 circRNAs were correlated with autophagy in myocardial tissue after SICM. Of these, 179 circRNAs were predicted to function as "miRNA sponges". Some distinctive circRNAs and mRNAs found by ceRNA analysis might be involved in autophagy in SICM. These findings provide insights into circRNAs and identified new research targets that may be used to further explore the pathogenesis of SICM.

IFN-γ-STAT1-mediated CD8+ T-cell-neural stem cell cross talk controls astrogliogenesis after spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) causes nearly all patients to suffer from protracted disabilities. An emerging therapeutic strategy involving the recruitment of endogenous neural stem cells (NSCs) has been developed. However, endogenous NSCs in the adult spinal cord differentiate into mostly astrocytes after traumatic injury, forming glial scars, which is a major cause of regeneration failure in SCI. Thus, understanding which factors drive the activation and differentiation of endogenous NSCs after SCI is critical for developing therapeutic drugs. METHODS: The infiltration, state, and location of CD8+ T cells in spinal cord after traumatic injury were analyzed by flow cytometry and immunofluorescence (IF) staining. The Basso Mouse Scale (BMS) scores and rotarod testing were used for motor behavioral analysis. NSCs were co-cultured with CD8+ T cells. EdU assay was used to detect proliferative cells. Western blotting was used to analyze the expression levels of STAT1, p-STAT1, and p27. ChIP-seq and ChIP-qRT-PCR analyses were used to detect the downstream of STAT1. Nestin-CreERT2::Ai9 transgenic mice were used to genetic lineage tracing of Nestin+ NSCs after SCI in vivo. RESULTS: A prolonged increase of activated CD8+ T cells occurs in the injured spinal cords. The behavioral analysis demonstrated that the administration of an anti-CD8 antibody promotes the recovery of locomotor function. Then, we discovered that CD8+ T cells suppressed the proliferation of NSCs and promoted the differentiation of NSCs into astrocytes by the IFN-γ-STAT1 pathway in vitro. ChIP-seq and ChIP-qRT-PCR analysis revealed that STAT1 could directly bind to the promoters of astrocyte marker genes GFAP and Aldh1l1. Genetic lineage tracing of Nestin+ NSCs demonstrated that most NSCs differentiated into astrocytes following SCI. Depleting CD8+ T cells reduced the differentiation of NSCs into astrocytes and instead promoted the differentiation of NSCs into oligodendrocytes. CONCLUSION: In conclusion, CD8+ T cells suppressed the proliferation of NSCs and promoted the differentiation of NSCs into astrocytes by the IFN-γ-STAT1-GFAP/Aldhl1l axis. Our study identifies INF-γ as a critical mediator of CD8+ T-cell-NSC cross talk and a potential node for therapeutic intervention in SCI.

An Apriori Algorithm-Based Association Analysis of Analgesic Drugs in Chinese Medicine Prescriptions Recorded From Patients With Rheumatoid Arthritis Pain.

Chronic pain, a common symptom of people with rheumatoid arthritis, usually behaves as persistent polyarthralgia pain and causes serious damage to patients' physical and mental health. Opioid analgesics can lead to a series of side effects like drug tolerance and addiction. Thus, seeking an alternative therapy and screening out the corresponding analgesic drugs is the key to solving the current dilemma. Traditional Chinese Medicine (TCM) therapy has been recognized internationally for its unique guiding theory and definite curative effect. In this study, we used the Apriori Algorithm to screen out potential analgesics from 311 cases that were treated with compounded medication prescription and collected from "Second Affiliated Hospital of Zhejiang Chinese Medical University" in Hangzhou, China. Data on 18 kinds of clinical symptoms and 16 kinds of Chinese herbs were extracted based on this data mining. We also found 17 association rules and screened out four potential analgesic drugs-"Jinyinhua," "Wugong," "Yiyiren," and "Qingfengteng," which were promised to help in the clinical treatment. Besides, combined with System Cluster Analysis, we provided several different herbal combinations for clinical references.

Resveratrol suppresses microglial activation and promotes functional recovery of traumatic spinal cord via improving intestinal microbiota.

Spinal cord injury (SCI) can change the intestinal microbiota pattern and corresponding metabolites, which in turn affect the prognosis of SCI. Among many metabolites, short-chain fatty acids (SCFAs) are critical for neurological recovery after SCI. Recent research has shown that resveratrol exerts anti-inflammatory properties. But it is unknown if the anti-inflammatory properties of resveratrol are associated with intestinal microbiota and metabolites. We thus investigate the alteration in gut microbiota and the consequent change of SCFAs following resveratrol treatment. The SCI mouse models with retention of gut microbiota (donor) and depletion of gut microbiota (recipient) were established. Fecal microbiota transplantation from donors to recipients was performed with intragastrical administration. Spinal cord tissues of mice were examined by H&E, Nissl, and immunofluorescence stainings. The expressions of the inflammatory profile were examined by qPCR and cytometric bead array. Fecal samples of mice were collected and analyzed with 16S rRNA sequencing. The results showed that resveratrol inhibited the microglial activation and promoted the functional recovery of SCI. The analysis of intestinal microbiota and metabolites indicated that SCI caused dysbiosis and the decrease in butyrate, while resveratrol restored microbiota pattern, reversed intestinal dysbiosis, and increased the concentration of butyrate. Both fecal supernatants from resveratrol-treated donors and butyrate suppressed the expression of pro-inflammatory genes in BV2 microglia. Our result demonstrated that fecal microbiota transplantation from resveratrol-treated donors had beneficial effects on the functional recovery of SCI. One mechanism of resveratrol effects was to restore the disrupted gut microbiota and butyrate.

Macrophages induce cardiomyocyte ferroptosis via mitochondrial transfer.

INTRODUCTION: Mitochondrial transfer is a new cell-to-cell communication manner. Whether the mitochondrial transfer is also involved in the macrophage infiltration-induced cardiac injury is unclear. OBJECTIVES: This study aimed to determine whether macrophage mitochondria can be transferred to cardiomyocytes, and to investigate its possible role and mechanism. METHODS: Mitochondrial transfer between macrophages and cardiomyocytes was detected using immunofluorescence staining and flow cytometry. Cellular metabolites were analyzed using LC-MS technique. Differentially expressed mRNAs were identified using RNA-seq technique. RESULTS: (1) After cardiomyocytes were cultured with macrophage-conditioned medium (COND + group), macrophage-derived mitochondria have been found in cardiomyocytes, which could be blocked by dynasore (an inhibitor of clathrin-mediated endocytosis). (2) Compared with control (CM) group, there were 545 altered metabolites found in COND + group, most of which were lipids and lipid-like molecules. The altered metabolites were mainly enriched in the ß-oxidation of fatty acids and glutathione metabolism. And there were 4824 differentially expressed mRNAs, which were highly enriched in processes like lipid metabolism-associated pathway. (3) Both RNA-seq and qRT-PCR results found that ferroptosis-related mRNAs such as Ptgs2 and Acsl4 increased, and Gpx4 mRNA decreased in COND + group (P < 0.05 vs CM group). (4) The levels of cellular free Fe2+ and mitochondrial lipid peroxidation were increased; while GSH/GSSG ratio, mitochondrial aspect ratio, mitochondrial membrane potential, and ATP production were decreased in cardiomyocytes of COND + group (P < 0.05 vs CM group). All the above phenomena could be blocked by a ferroptosis inhibitor ferrostatin-1 (P < 0.05). CONCLUSION: Macrophages could transfer mitochondria to cardiomyocytes. Macrophage-derived mitochondria were internalized into cardiomyocytes through clathrin- and/or lipid raft-mediated endocytosis. Uptake of exogenous macrophage mitochondria induced cardiomyocyte injury via triggering ferroptosis.

Single-cell transcriptome analysis reveals the immune heterogeneity and the repopulation of microglia by Hif1α in mice after spinal cord injury.

Neuroinflammation is regarded as a vital pathological process in spinal cord injury (SCI), which removes damaged tissue, secretes cytokines, and facilitates regeneration. Repopulation of microglia has been shown to favor recovery from SCI. However, the origin and regulatory factors of microglia repopulation after SCI remain unknown. Here, we used single-cell RNA sequencing to portray the dynamic transcriptional landscape of immune cells during the early and late phases of SCI in mice. B cells and migDCs, located in the meninges under physiological conditions, are involved in immune surveillance. Microglia quickly reduced, and peripheral myeloid cells infiltrated three days-post-injury (dpi). At 14 dpi, microglia repopulated, myeloid cells were reduced, and lymphocytes infiltrated. Importantly, genetic lineage tracing of nestin+ and Cx3cr1+ cells in vivo showed that the repopulation of microglia was derived from residual microglia after SCI. We found that residual microglia regress to a developmental growth state in the early stages after SCI. Hif1α promotes microglial proliferation. Conditional ablation of Hif1α in microglia causes larger lesion sizes, fewer axon fibers, and impaired functional recovery in the late stages after SCI. Our results mapped the immune heterogeneity in SCI and raised the possibility that targeting Hif1α may help in axon regeneration and functional recovery after SCI.

Butorphanol alleviates lipopolysaccharide-induced inflammation and apoptosis of cardiomyocytes via activation of the κ-opioid receptor.

Sepsis-induced myocardial dysfunction is a leading cause of the high mortality rates associated with sepsis. The aim of the present study was to investigate the effect of butorphanol on sepsis-induced cardiomyocyte dysfunction. Lipopolysaccharide (LPS) was used to induce H9C2 cardiomyocytes to establish an in vitro sepsis model. The effect of butorphanol on the viability of LPS-induced H9C2 cells was analyzed using a Cell Counting Kit-8 assay. The levels of tumor necrosis factor-α, interleukin (IL)-1ß and IL-6 were detected using ELISA. Western blotting was used to analyze the expression levels of inflammation-and apoptosis-related proteins. Cell apoptosis was measured using a TUNEL assay. The expression levels of κ-opioid receptor (KOR) were analyzed using reverse transcription-quantitative PCR analysis and western blotting. Following LPS induction, the levels of inflammatory cytokines and proapoptotic proteins were found to be upregulated in H9C2 cells, while butorphanol treatment downregulated these levels. The expression levels of KOR were also upregulated following butorphanol treatment in LPS-induced H9C2 cells. Addition of the KOR inhibitor, nor-binaltorphimine, alleviated the inhibitory effects of butorphanol on inflammation and apoptosis in LPS-induced H9C2 cells. In conclusion, the findings of the present study provided evidence indicating that butorphanol may alleviate LPS-induced inflammation and apoptosis in cardiomyocytes by upregulating KOR expression, which may provide a novel insight into the potential therapeutic effects of butorphanol and its underlying mechanism of action.

Propofol alleviates inflammation and apoptosis in HCY­induced HUVECs by inhibiting endoplasmic reticulum stress.

Atherosclerosis is a chronic vascular inflammatory disease, and is associated with oxidative stress and endothelial dysfunction. Homocysteine (HCY) can cause damage to endothelial cells via the enhancement of the endoplasmic reticulum stress (ERS) pathway. Propofol has a protective effect on endothelial injury and can suppress inflammation and oxidation. The purpose of the present study was to investigate the protective effect of propofol on HCY­induced inflammation and apoptosis of human umbilical vein endothelial cells  (HUVECs). HCY was used to establish the endothelial injury model. Cell Counting Kit­8 assays and flow cytometry were used to detect cell viability and apoptosis, respectively. Then, ELISA was performed to examine the expression levels of inflammatory cytokines, and the expression levels of proteins related to inflammation, apoptosis and ERS were determined via western blotting. Results showed that propofol increased cell viability, suppressed NF­κB signaling pathway activation and decreased the expression levels of inflammatory factors in HUVECs induced by HCY. Moreover, propofol could inhibit the expression of proteins involved in ERS, including ER chaperone BiP (Bip), C/EBP­homologous protein, protein kinase R­like ER kinase and inositol­requiring 1α, and reduce cell apoptosis of HCY­induced HUVECs. However, the overexpression of Bip could reactivate ERS and the NF­κB signaling pathway, as well as promote inflammation and cell apoptosis, when compared with HCY­treated groups. In conclusion, propofol can ameliorate inflammation and cell apoptosis of HUVECs induced by HCY via inhibiting ERS, which may provide a novel insight into the treatment of atherosclerosis.

Identification of mitochondrial function-associated lncRNAs in septic mice myocardium.

The present study aimed to analyze long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in septic mice heart and to identify potential lncRNAs and mRNAs that be responsible for cardiac mitochondrial dysfunction during sepsis. Mice were treated with 10 mg/kg of lipopolysaccharides to induce sepsis. LncRNAs and mRNAs expression were evaluated by using lncRNA and mRNA microarray or real-time polymerase chain reaction technique. LncRNA-mRNA coexpression network assay, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed. The results showed that 1275 lncRNAs were differentially expressed in septic myocardium compared with those in the control group. A total of 2769 mRNAs were dysregulated in septic mice heart, most of which are mainly related to the process of inflammation, mitochondrial metabolism, oxidative stress, and apoptosis. Coexpression network analysis showed that 14 lncRNAs were highly correlated with 11 mitochondria-related differentially expressed mRNA. Among all lncRNAs and their cis-acting mRNAs, 41 lncRNAs-mRNA pairs (such as NONMMUG004378 and Apaf1 gene) were enriched in GO terms and KEGG pathways. In summary, we gained some specific lncRNAs and their potential target mRNAs that might be involved in mitochondrial dysfunction in septic myocardium. These findings provide a panoramic view of lncRNA and might allow developing new treatment strategies for sepsis.

MCC950 Reduces Neuronal Apoptosis in Spinal Cord Injury in Mice.

BACKGROUND: Traumatic Spinal Cord Injury (SCI) is a severe condition usually accompanied by an inflammatory process that gives rise to uncontrolled local apoptosis and a subsequent unfavorable prognosis. One reason for this unfavorable outcome could be the activation of the NLRP3 inflammasome. OBJECTIVE: MCC950 is a specific inhibitor of NLRP3 that further inhibits the formation of the NLRP3 inflammasome. The purpose of this study was to determine whether the NLRP3 inflammasome was associated with the severity of local apoptosis and whether MCC950 could prevent neuronal apoptosis following SCI. METHODS: In this study, primary cortical neurons were cultured in vitro. With or without pretreatment/ posttreatment with MCC950, neurons were subjected to Oxygen-Glucose Deprivation (OGD) for 2 h and then reperfusion for 20 h. Immunofluorescence was used to determine the expression of NLRP3, ASC, and cleaved caspase-1 in neurons. In vivo, SCI model mice were established with a 5 g weight-drop method. MCC950 was intraperitoneally injected at 0, 2, 4, 6, 8, 10, and 12 days after SCI. Basso Mouse Scale (BMS) scores and footprint assays were used to assess motor function. Paw withdrawal threshold and tail-flick latency were used to assess somatosensory function. H&E, Nissl, and TUNEL staining were used to measure histological changes and apoptosis at 3 days after SCI, and scar formation was observed by Masson staining and GFAP immunohistochemical analysis at 28 days after SCI. RESULTS: Immunofluorescence analysis confirmed that MCC950 inhibited OGD-induced activation of the NLRP3 inflammasome in neurons. Behavioral tests, Masson staining, and GFAP immunohistochemical analysis showed that MCC950-treated mice had improved neuronal functional recovery and reduced scar formation at 28 days after SCI. H&E, Nissl, and TUNEL staining confirmed that there were more living neurons and fewer apoptotic neurons in MCC950-treated mice than control mice at 3 days after SCI. CONCLUSION: These results reveal that MCC950 exerts neuroprotective effects by reducing neuronal apoptosis, preserving the survival of the remaining neurons, attenuating the severity of the damage, and promoting the recovery of motor function after SCI.

Microarray assay of circular RNAs reveals cicRNA.7079 as a new anti-apoptotic molecule in spinal cord injury in mice.

Traumatic spinal cord injury (SCI) can lead to motor disturbance, sensory deficit, or autonomic dysfunction. The role of circRNAs in the pivotal physiopathological processes of SCI has been demonstrated recently. However, no similar research has been performed to explore the circRNAs involved in apoptosis after SCI. The differentially expressed circRNAs in mice spinal cord three days after SCI were originally detected with microarray assay (n = 4/group). Subsequently, potential apoptosis-related circRNAs were predicted by comprehensive bioinformatics analysis. In total, 1131 circRNAs varied (>2-fold change, p < 0.05) in the injured mice spinal cord. The characters of these circRNAs were summarized. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was applied to predict the primary function of these circRNAs. 148 circRNAs were found to be correlated to the apoptosis injury progress in after SCI. Moreover, an apoptosis-related ceRNA network was constructed. In loss-of-function experiments, cicRNA.7079 knockdown enhanced apoptosis in NSC-34 motor neurons. This study may contribute to new insights into the mechanism of apoptosis after SCI. The anticipation of anti-apoptosis circRNA. 7079 may provide potential research targets for SCI in mice.

RGFP966 inactivation of the YAP pathway attenuates cardiac dysfunction induced by prolonged hypothermic preservation.

Oxidative stress and apoptosis are the key factors that limit the hypothermic preservation time of donor hearts to within 4-6 h. The aim of this study was to investigate whether the histone deacetylase 3 (HDAC3) inhibitor RGFP966 could protect against cardiac injury induced by prolonged hypothermic preservation. Rat hearts were hypothermically preserved in Celsior solution with or without RGFP966 for 12 h followed by 60 min of reperfusion. Hemodynamic parameters during reperfusion were evaluated. The expression and phosphorylation levels of mammalian STE20-like kinase-1 (Mst1) and Yes-associated protein (YAP) were determined by western blotting. Cell apoptosis was measured by the terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Addition of RGFP966 in Celsior solution significantly inhibited cardiac dysfunction induced by hypothermic preservation. RGFP966 inhibited the hypothermic preservation-induced increase of the phosphorylated (p)-Mst1/Mst1 and p-YAP/YAP ratios, prevented a reduction in total YAP protein expression, and increased the nuclear YAP protein level. Verteporfin (VP), a small molecular inhibitor of YAP-transcriptional enhanced associate domain (TEAD) interaction, partially abolished the protective effect of RGFP966 on cardiac function, and reduced lactate dehydrogenase activity and malondialdehyde content. RGFP966 increased superoxide dismutase, catalase, and glutathione peroxidase gene and protein expression, which was abolished by VP. RGFP966 inhibited hypothermic preservation-induced overexpression of B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and cleaved caspase-3, increased Bcl-2 mRNA and protein expression, and reduced cardiomyocyte apoptosis. The antioxidant and anti-apoptotic effects of RGFP966 were cancelled by VP. The results suggest that supplementation of Celsior solution with RGFP966 attenuated prolonged hypothermic preservation-induced cardiac dysfunction. The mechanism may involve inhibition of oxidative stress and apoptosis via inactivation of the YAP pathway.

Rapid and label-free urine test based on surface-enhanced Raman spectroscopy for the non-invasive detection of colorectal cancer at different stages.

The concept of being able to urinate in a cup and screen for colorectal cancer (CRC) is fascinating to the public at large. Here, a simple and label-free urine test based on surface-enhanced Raman spectroscopy (SERS) was employed for CRC detection. Significant spectral differences among normal, stages I-II, and stages III-IV CRC urines were observed. Using discriminant function analysis, the diagnostic sensitivities of 95.8%, 80.9%, and 84.3% for classification of normal, stages I-II, and stages III-IV CRC were achieved in training model, indicating the great promise of urine SERS as a rapid, convenient and noninvasive method for CRC staging detection.

Dimethyl fumarate attenuates lipopolysaccharide-induced mitochondrial injury by activating Nrf2 pathway in cardiomyocytes.

AIMS: To determine whether dimethyl fumarate (DMF) can protect against lipopolysaccharide (LPS) -induced myocardial injury. MAIN METHODS: H9c2 cells pretreated with or without DMF were stimulated with LPS. Cell viability and apoptosis were evaluated. Nrf2 and HO-1 expression were detected using Western blotting. Mitochondrial morphology, mitochondrial superoxide production were observed using confocal microscope. Mitochondrial respiration function was measured using Seahorse bioanalyzer. KEY FINDINGS: (1) The cell viability decreased, LDH release and apoptosis increased in LPS- challenged H9c2 cells. DMF pretreatment brought a higher cell viability, and a lower LDH leakage and apoptosis than those of LPS group (P < 0.01). (2) DMF pretreatment resulted in an increased Nrf2 and HO-1 expression, and enhanced nuclear Nrf2 level in LPS-challenged cells (P < 0.01). (3) Nrf2-siRNA could inhibit DMF-induced enhancement of HO-1 expression and cell viability, and partly abolish DMF-induced reduction of LDH leakage and apoptosis. (4) ERK1/2 inhibitor PD98059 could not only prevent the DMF-induced enhancement of nuclear Nrf2 and HO-1, but also inhibit DMF-induced increase in cell viability. (5) Compared with LPS-challenged cells, DMF pretreatment caused a lower production of mitochondrial superoxide and a higher mitochondrial membrane potential, which could be abolished by Nrf2-siRNA. (6) DMF could attenuate LPS-induced mitochondrial fragmentation and improve mitochondrial respiration function by enhancement of the oxygen consumption rate of basal respiration and ATP production in LPS-challenged cells (P < 0.01). SIGNIFICANCE: DMF protects cardiomyocytes against LPS-induced damage. ERK1/2-dependent activation of Nrf2/HO-1 pathway is responsible for DMF-induced cardioprotection via reduction of oxidative stress, improvement of mitochondrial morphology and energy metabolism.

Assessment of the anti-inflammatory, analgesic and sedative effects of oleuropein from Olea europaea L.

More and more studies show that inflammation, pain and insomnia have become the main common diseases. Effective treatments of inflammation, pain and insomnia have become an issue of primary concern in clinical practice. Oleuropein (OLE), the main phenolic component of Mediterranean extra virgin olive oil, has shown many pharmacological properties. In the present study, the anti-inflammatory effect of OLE was firstly evaluated using RAW264.7 macrophages subjected to stimulation with lipopolysaccharide (LPSC). The results obtained revealed that OLE caused significant and dose-dependent downregulation of nitric (NO), COX-2, inducible NO synthase iNOS, and the inflammation-associated cytokines IL-6 and TNF-α. From the mechanism, the expression of COX-2, cytokines IL-6 and TNF-α OLE is closely related to analgesic and sedation effect. Further evaluations showed significant analgesic and sedative effects of OLE in tail-flick test and sedation test conducted in SD rats in vivo. All these results indicate that OLE has anti-inflammatory, analgesic and sedative effects both in vitro and in vivo.

Local application of MDL28170-loaded PCL film improves functional recovery by preserving survival of motor neurons after traumatic spinal cord injury.

Neuronal death and organization degeneration can happen inordinately after spinal cord injury (SCI), which lead to nerve dysfunction. We aimed to determine whether local application of a cell permeable calpain I inhibitor (MDL28170) can promote SCI recovery by increasing neuronal cell viability. MDL28170-loaded polycaprolactone (PCL) film was fabricated. Scanning electron microscopy showed the surface of PCL film was smooth with holes (diameter at µM level). The PCL film was non-toxic, biological compatibility, and had good neuron adhension and slow release characteristic. MDL28170 increased VSC4.1 motor neurons' viability under tunicamycin (an endoplasmic reticulum stress) induced injury. In a traumatic SCI rat model, MDL28170-loaded PCL film reduced the area of lesion cavity, and promoted recovery of locomotor behavior. Moreover, the expression of GAP-43 was upregulated after MDL28170-loaded PCL film treatment. Thus, our findings demonstrated that localized delivery of MDL28170 could promote SCI recovery by inhibiting endoplasmic reticulum stress, preserving survival of the motor neurons, which may point out a promising therapeutic target for treating SCI patient.

Linagliptin improved myocardial function recovery in rat hearts after a prolonged hypothermic preservation.

AIMS: To determine whether linagliptin, a dipeptidyl peptidase 4 inhibitor, can promote the recovery of cardiac function after hypothermic preservation. MAIN METHODS: Rat hearts were preserved in cold Celsior solution with or without linagliptin for 9 h. Cardiac function was evaluated at 60 min of reperfusion after hypothermic preservation. Cardiac mitochondrial morphology was observed using transmission electron microscope. The expression of dynamin-related protein 1 (Drp1), NADPH oxidase 2 (NOX2), calmodulin-dependent protein kinase II (CaMKII) were detected using Western blot. KEY FINDINGS: Compared with Celsior group, supplement of Celsior solution with linagliptin (0.25-0.75 nM) could significantly prevent hypothermic preservation-induced cardiac dysfunction. The expression of NOX2 protein, ROS level and MDA content in cardium were increased after hypothermic preservation, which was inhibited by linagliptin. Although the mitofusin1, 2, optic atrophy type 1, and total Drp1 expression in myocardium did not change, the level of p-Drp1 S616 and mitochondrial Drp1 were enhanced after hypothermic preservation. Linagliptin supplement could inhibit the hypothermic preservation-induced increase in p-Drp1 S616 and mitochondrial Drp1 protein, and mitigate the mitochondrial fragmentation. Level of p-CaMKII protein enhanced after hypothermic preservation, which could be prevented by linagliptin or a NOX2 inhibitor Phox-I2. Both Phox-I2 and a CaMKII inhibitor KN-93 could reduce the hypothermic preservation-induced increase in p-Drp1 S616 and mitochondrial Drp1 protein. SIGNIFICANCE: Supplement Celsior solution with linagliptin could improve cardiac function recovery in 9-h hypothermic preserved rat hearts. The cardioprotective effect of linagliptin might be due to the inhibition of Drp1 phosphorylation and mitochondrial translocation by preventing NOX2-mediated CaMKII activation.